1. Field of the Invention
The present invention relates to sulfatase inhibitors and methods for making and using the same. These methods include use of these compounds in therapeutic and prophylactic treatments for estrogen dependent illnesses.
2. Background Information
Estrogen levels in breast tumors of post-menopausal women are at least ten times higher than estrogen levels in plasma. The high levels of estrogen in these tumors are due to in situ formation of estrogen, possibly through conversion of estrone sulfate to estrone by the enzyme estrone sulfatase. Inhibitors of estrone sulfatase are therefore potential agents for the treatment of estrogen-dependent breast cancers. Most estrone sulfatase inhibitors are steroidal in nature. Although estrone-3-O-sulfamate (EMATE) is believed to be the most potent inhibitor of estrone sulfatase, recent evidence indicates that this compound is a potent estrogen. This compound is therefore not useful in the treatment of estrogen dependent illnesses.
Reed and co-workers reported on sulfatase inhibitory activities of estrone-3-O-methylthiophosphonate, estrone-3-O alkyl and aryl sulfonates, estrone-3-O-phosphonates and thiophosphonates and estrone sulfamates in: Duncan et al., "Inhibition of estrone sulfate activity by estrone-3-methylthiophosphonate", Cancer Res. 53:298-303 (1993); Howarth et al., "Phosphonates and thiophosphonates as sulfate surrogates: Synthesis of estrone-3-methylthiophosphonate, a potent inhibitor of estrone sulfatase", Bioorg. Med. Chem. Lett. 3:313-318 (1993); Howarth et al., "Estrone sulfamates: Potent inhibitors of estrone sulfatase with therapeutic potential", J. Med. Chem. 37:219-221 (1994); and Purohit, et al., "In vivo inhibition of Oesterone Sulphatase and Dehydoepiandrosterone Sulphatase by Oestrone-3-O-sulphamate", Int. J. Cancer, 63:106-111 (1995).
Li and co-workers reported the synthesis and sulfatase inhibitory activities of sulfonate and its analogues, methylene sulfonates and phosphate that contain the estrone nucleus in Li et al., "Synthesis and biochemical studies of estrone sulfatase inhibitors", Steroids, 58:106-111 (1993); Dibbelt et al, "Inhibition of human placental sterylsulfatase by synthetic analogues of estrone sulfate", J. Steroid Biochem. Molec. Biol., 52 (3):281-286 (1995); and Li et al., "Estrone sulfate analogues as estrone sulfatase inhibitors", Steroids 60:299-306 (1995). Estrone-3-amino derivatives are reported in Selcer et al., "Inhibition of Placental Estrone Sulfatase Activity and MCF-7 Breast Cancer Cell Proliferation by Estrone-3-amino Derivatives", J. Steroid Biochem. Molec. Biol., 59:83-91 (1996).
U.S. Pat. No. 5,567,831 is directed to the use of non-steroidal sulfatase inhibitor compounds in the treatment of estrogen dependent illnesses.
U.S. Pat. No. 5,571,933 is directed to derivatives of estra 1,3,5(10)triene-17-one, 3-amino compounds and methods for using these compounds in the treatment of estrogen dependent illnesses.
U.S. Pat. No. 5,556,847 is directed to steroidal sulfatase inhibitors and methods for using these inhibitors to effect memory enhancement. Use of these inhibitors in the treatment of estrogen dependent illnesses is not disclosed.
U.S. Pat. No. 5,616,574 discloses steroid sulphatase inhibitors and the methods of using the same. The disclosed compounds do not include the C17 substituted 1,3,5,(10) triene compounds of the present invention. The compounds are potent estrogens and metabolize to form estrones, which further distinguishes them from the compounds of the present invention which do not metabolize to form estrones.
There remains a need, therefore, for potent sulfatase inhibitors that are metabolically stable, more selective and devoid of estrogenic activity.